Compositions having an inner core and at least two surrounding layers

ABSTRACT

The disclosure relates to compositions comprising an inner core and at least two surrounding layers. The compositions are suitable for use in humans and other mammals, particularly wherein a component of the inner core is susceptible to moisture. In particular, the disclosed compositions comprise:  
     (a) an inner core comprising one or more components;  
     (b) an inner layer which surrounds the inner core, wherein the inner layer is selected from the group consisting of continuous coatings insoluble at a pH of about 3 or less, continuous coatings having a coating weight of from about 3 mg/cm 2  to about 25 mg/cm 2 , and combinations thereof; and  
     (c) an outer layer which surrounds the inner layer, wherein the outer layer is hydrophobic.

FIELD OF THE INVENTION

[0001] The present invention relates to compositions that are useful foradministration to humans and other mammals. The compositions areparticularly useful wherein the composition comprises a component thatis susceptible to moisture or may otherwise be compromised byenvironmental factors. The compositions comprise an inner core and atleast two surrounding layers, wherein the surrounding layers protect theinner core from moisture or such other factors.

BACKGROUND OF THE INVENTION

[0002] The delivery of biologically active components that aresusceptible to moisture or are otherwise compromised by environmentalfactors has been a continuous problem for those presented with thechallenge of formulating such components in a stable product. Indeed, avariety of mechanisms have been proposed, for example, encapsulation ofhygroscopic materials or inclusion of agents such as dessicants.However, these mechanisms on their own may not always be suitable oreffective for use.

[0003] Even further, many components are desirable for delivery tospecific locations in the mammalian system, for example, the jejunem,ileum, or other locations in the intestinal tract. Such components areoften enterically coated for targeted intestinal delivery and preventionof degradation in acidic environments such as the stomach. However, suchenteric coatings may not be effective in preventing moisture fromaffecting, or coming in contact with, the susceptible component.

[0004] For example, it has recently been reported that certain probioticcomponents that are isolated from healthy gastrointestinal tracts areuseful for treating inflammatory conditions such as inflammatory boweldisease or irritable bowel syndrome. Indeed, successful delivery of suchcomponents to the inflamed portions of the gastrointestinal tract, forexample the intestines, is likely to be an important advance in treatingthese conditions. However, oral administration of such components hasproven challenging, as such probiotic components necessarily passthrough non-native locations of the gastrointestinal tract, for examplethe acidic environment of the stomach, where the probiotic componentscan be quickly degraded. Moreover, the shelf stability of suchcomponents, perhaps primarily due to susceptibility to moisture, may notbe suitable or practical for product manufacturers.

[0005] As a result, there is a continuing need for compositions that areuseful for maintaining the integrity of susceptible probiotics and othercomponents such as vitamins and certain other sensitive biologicallyactive agents. Surprisingly, the present inventors have discoveredcompositions which are suitable for effective delivery of one or more ofsuch susceptible components. The inventors have discovered thatcompositions comprising at least two layers surrounding the core whichcontains the component, wherein the layers are an enteric layer and ahydrophobic layer, respectively, provide surprisingly optimizedstability. Such compositions are suitable for use with susceptiblecomponents such as probiotics, even wherein an extended shelf life isnecessary for commercial delivery. These and other benefits of thepresent invention are described herein below.

SUMMARY OF THE INVENTION

[0006] The present invention relates to compositions containing an innercore and at least two surrounding layers. The compositions are suitablefor use in humans and other mammals, particularly wherein a component ofthe inner core is susceptible to moisture. In particular, the presentinvention relates to compositions comprising:

[0007] (a) an inner core comprising one or more components;

[0008] (b) an inner layer which surrounds the inner core, wherein theinner layer is selected from the group consisting of continuous coatingsinsoluble at a pH of about 3 or less, continuous coatings having acoating weight of from about 3 mg/cm² to about 25 mg/cm², andcombinations thereof; and

[0009] (c) an outer layer which surrounds the inner layer, wherein theouter layer is hydrophobic.

[0010] In a preferred embodiment of the present invention, the innercore comprises bacteria. Preferred bacteria for use herein include thoseselected from lactobacillus, bifidobacteria, and mixtures thereof, andother bacteria that are susceptible to moisture or may be otherwisecompromised by environmental factors.

DETAILED DESCRIPTION OF THE INVENTION

[0011] Various documents including, for example, publications andpatents, are recited throughout this disclosure. All such documents arehereby incorporated by reference. The citation of any given document isnot to be construed as an admission that it is prior art with respect tothe present invention.

[0012] All percentages and ratios are calculated by weight unlessotherwise indicated. All percentages and ratios are calculated based onthe total composition unless otherwise indicated.

[0013] Referenced herein are trade names for components includingvarious ingredients utilized in the present invention. The inventorsherein do not intend to be limited by materials under a certain tradename. Equivalent materials (e.g., those obtained from a different sourceunder a different name or reference number) to those referenced by tradename may be substituted and utilized in the descriptions herein.

[0014] In the description of the invention various embodiments orindividual features are disclosed. As will be apparent to the ordinarilyskilled practitioner, all combinations of such embodiments and featuresare possible and can result in preferred executions of the presentinvention.

[0015] The compositions herein may comprise, consist essentially of, orconsist of any of the features or embodiments as described herein.

[0016] While various embodiments and individual features of the presentinvention have been illustrated and described, various other changes andmodifications can be made without departing from the spirit and scope ofthe invention. As will also be apparent, all combinations of theembodiments and features taught in the foregoing disclosure are possibleand can result in preferred executions of the invention.

COMPOSITIONS OF THE PRESENT INVENTION

[0017] The present invention relates to compositions that are useful foradministration to humans and other mammals. The compositions areparticularly useful wherein the inner core of the composition comprisesa component that is susceptible to moisture or may otherwise becompromised by environmental factors. The compositions comprise theinner core and at least two surrounding layers, wherein the surroundinglayers protect the inner core from moisture or such other factors.

[0018] The present compositions comprise:

[0019] (a) an inner core comprising one or more components;

[0020] (b) an inner layer which is contiguous with the inner core,wherein the inner layer is selected from the group consisting ofcontinuous coatings insoluble at a pH of about 3 or less, continuouscoatings having a coating weight of from about 3 mg/cm² to about 25mg/cm², and combinations thereof; and

[0021] (c) an outer layer which surrounds the inner layer, wherein theouter layer is hydrophobic.

[0022] As used herein, the inner layer and outer layer are differentcompositions relative to each other, i.e., the inner layer does not havethe same total chemical composition as the outer layer. Each of theelements of the present invention, including preferred embodiments aredescribed herein as follows:

[0023] Definitions

[0024] The layers herein are each joined to the inner core. As usedherein, the terms “joined to,” “joined to the inner core,” or the likemeans surrounding the inner core in such a manner that the layer iscontiguous with either the inner core itself, a preceding layer, or asucceeding layer. The layer may be “joined to” the inner core, apreceding layer, or a succeeding layer even though other matter (such asanother preceding or succeeding layer) intervenes. Accordingly, a layerwhich is “joined to” the inner core need not actually be contiguous withthe inner core.

[0025] As used herein, the term “contiguous with” means directly joinedby physical forces with essentially no intervening matter. For example,the inner layer may be contiguous with the inner core as well as asucceeding layer (wherein the succeeding layer is either another layeror the outer layer). As another example, the outer layer may becontiguous with the inner layer or another layer. The outer layer is notcontiguous with the inner core, because the inner layer is a precedinglayer relative to the outer layer.

[0026] As used herein, the term “preceding layer” means a layer which isjoined to the inner core and is closer in proximity to the inner corerelative to a reference layer joined to the same inner core. Forexample, the inner layer is a preceding layer relative to the outerlayer.

[0027] As used herein, the term “succeeding layer” means a layer whichis joined to the inner core but is further in proximity from the innercore relative to a reference layer joined to the same inner core. Forexample, the outer layer is a succeeding layer relative to the innerlayer.

[0028] As used herein, coating weights are expressed in terms of mg/cm²,referring to milligrams (mg) of referenced layer per square centimeter(cm²) of referenced layer.

[0029] The Inner Core

[0030] The inner core comprises one or more components. The componentsmay be any of a variety of materials. A component may be selected from,for example, biologically active components including drug substances,over-the-counter substances, nutriceuticals, dietary supplements, andcombinations thereof. Specifically, a component may be selected from,for example, bacteria, vitamins, minerals, fibers, and otherbiologically active components. A component may also be an excipient,including those that are combined in the composition with a biologicallyactive component.

[0031] Preferably, at least one of the components is susceptible tomoisture or is otherwise ordinarily compromised by environmentalfactors. For example, one or more hygroscopic materials may be utilized,as it has been discovered that the present invention is quite suitablefor creating a water impermeable barrier. As another preferredembodiment herein, at least one of the components has a water activityof about 0.3 or less, alternatively about 0.2 or less, as measured at atemperature of from about 20° C. to about 25° C. Measurement of wateractivity is standard in the art. For example, kits are readily availablefor use in the measurement of water activity, such as a water activitykit commercially available from Csiro, Australia.

[0032] In a preferred embodiment of the present invention, at least onecomponent of the inner core is prepared such that the inner core is alow water system. For example, at least one of the components may befreeze-dried, lyophilized, or spray-dried.

[0033] The component is also preferably desirable for delivery to themiddle and lower gastrointestinal tract, including the duodenum,jejunem, ileum, or colon.

[0034] In a preferred embodiment of the present invention, the innercore comprises bacteria. Preferably, the bacteria is a probioticmicroorganism. Probiotic microorganisms typically occur in the normal orhealthy intestines of humans or other mammals and have been shown tohave a beneficial effect on disturbed, diseased, and even healthygastrointestinal tracts of such mammals. However, probioticmicroorganisms may be susceptible to moisture or other environmentalfactors. The present invention therefore aids the delivery and efficacyof these microorganisms within the present compositions, since theinvention may protect against the degradation of the microorganismseither during storage or when administered to a mammal.

[0035] Preferably, the probiotic microorganisms are selected fromlactobacillus, bifidobacteria, streptococci, and mixtures thereof. Mostpreferably, the probiotic microorganisms are selected from the groupconsisting of lactobacillus, bifidobacteria, and mixtures thereof, forexample, Lactobacillus salivarius, Lactobacillus casei, Lactobacillusacidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus,Bifidobacterium bifidum, Bifidobacterium infantis, and mixtures thereof.Of these examples, Lactobacillus salivarius, Bifidobacterium infantis,or mixtures thereof are particularly preferred.

[0036] As a non-limiting example, strains of Bifidobacterium isolatedfrom resected and washed human gastrointestinal tract as described inCollins et al., WO 00/42168, published Jul. 20, 2000, are particularlypreferred. The Bifidobacterium infantis strain which is designated asUCC35624 is particularly preferred, described as being deposited at theNational Collections of Industrial and Marine Bacteria Limited (MCIMB)on Jan. 13, 1999 and accorded the accession number NCIMB 41003.

[0037] As another non-limiting example, strains of Lactobacillussalivarius isolated from resected and washed human gastrointestinaltract as described in Collins et al., WO 98/35014, published Aug. 13,1998, are particularly preferred. The Lactobacillus salivarius strainswhich are designated as UCC 1 and UCC 118 are each particularlypreferred, described as being deposited at the National Collections ofIndustrial and Marine Bacteria Limited (MCIMB) on Nov. 27, 1996 andaccorded the accession numbers NCIMB 40830 and 40829, respectively.

[0038] In one embodiment of the present invention, the compositions(most preferably, the inner core) comprise at least about 10⁶ cfu, morepreferably from about 10⁶ cfu to about 10¹⁵ cfu, even more preferablyfrom about 10⁷ to about 10¹³ cfu, and most preferably from about 10⁸ toabout 10¹² cfu of bacteria, all per gram of the inner core.

[0039] As other examples of inner core components, one or more vitaminsmay be utilized. Vitamin stability is often influenced by water activityin addition to other environmental factors. For example, vitamin A,vitamin B₁, vitamin B₂, vitamin B₆, vitamin B₁₂, niacin, folic acid,biotin, vitamin C, vitamin D, vitamin E, vitamin K, and mixtures thereofmay be used. Fat-soluble vitamins, for example beta-carotene and othersource of vitamin A, may be particularly useful for inclusion in theinner core due to their sensitivity to moisture. Vitamin C, vitamin E,and mixtures thereof are also particularly useful.

[0040] As yet another example of inner core components, one or moreenzymes may be utilized. For example, a proteolytic enzyme (e.g.,pancreatin) may be utilized.

[0041] Other non-limiting examples of components useful for the innercore include diclofenac, naproxen, aspirin, indomethacin, omeprazole,cardiac glycosides, electrolyte preparations with sodium, potassium, ormagnesium salts as well as calcium and iron preparations, bisacodylpreparations, valproic acid, 5-ASA, steroids such as hydrocortisone,budesonide, laxatives, octreotide, cisapride, anticholinergies, calciumchannel blockers, 5HT3-antagonists such as ondansetron and peptides suchas insulin.

[0042] As mentioned, a component of the inner core may be an excipient.Excipients are exceedingly well-known in the art. Non-limiting examplesof excipients include sweeteners (such as described herein below);flavor and/or coloring agents (such as described herein below),starches, such as corn starch and potato starch; cellulose and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose,and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solidlubricants, such as stearic acid and magnesium stearate; calciumsulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil,olive oil, corn oil and oil of theobroma; polyols such as propyleneglycol, glycerine, and polyethylene glycol; alginic acid; emulsifiers,such as TWEENS; wetting agents, such as sodium lauryl sulfate;tabletting agents such as binders, stabilizers; antioxidants; andpreservatives.

[0043] The inner core may be optionally formed into a tablet or othercompressed vehicle. Additionally or alternatively, the inner core may beencapsulated, wherein the composition is a capsule. A capsule layersurrounding the inner core, which is a preferred embodiment of thepresent invention, is discussed further herein below.

[0044] The Optional Capsule Layer

[0045] In an optional, but preferred embodiment of the presentinvention, the compositions comprise a capsule layer that surrounds andis joined to the inner core. Most preferably, this capsule layer iscontiguous to the inner core and is a preceding layer relative to theinner layer and outer layer. In this embodiment, the compositions areprovided in the form of tablets, capsules, or the like, preferablycapsules.

[0046] Preferably, the capsule layer comprises a component selected fromthe group consisting of gelatin (including modified gelatins, forexample, gelatin phthalate or gelatin succinate),hydroxypropylmethylcellulose (HPMC), starches, cellulosic polymers,other like polymers, and mixtures thereof. Most preferably, the capsulelayer comprises hydroxypropylmethylcellulose (HPMC). In a particularlypreferred embodiment of the present compositions, the capsule layerfurther comprises a plasticizer.

[0047] The capsule layers may be filled with the inner core according tostandard techniques or may otherwise be joined to the inner core. Forexample, the capsule layers may be provided, filled with the inner core,sealed if desired, and then further coated with the inner layer andouter layer. To illustrate, hard two-piece capsules may be sealed, forexample, via banding or LEMS (liquid encapsulation micro-spray,commercially available from Capsugel (Division of Warner-LambertCompany), Greenwood, S.C., U.S.A.).

[0048] The Inner Layer

[0049] The inner layer surrounds and is joined to the inner core. Theinner layer is selected from continuous coatings which are insoluble ata pH of about 3 or less, continuous coatings having a coating weight offrom about 3 mg/cm² to about 25 mg/cm², and combinations thereof. Asused herein, the term “continuous” means that the layer is not disruptedby a void at any point.

[0050] Preferably, the inner layer is a continuous coating which isinsoluble at a pH of about 3 or less, alternatively about 4 or less,alternatively about 5 or less. More preferably, such inner layer issoluble at a pH of about 5 or more, alternatively about 5.2 or more,alternatively about 5.5 or more. Most preferably, the inner layer is acontinuous coating which is soluble at a pH of from about 5 to about 7,alternatively from about 5.2 to about 6.8, alternatively from about 5.5to about 6.5. As used herein, the term “insoluble” means that at leastabout 75% of the referenced layer, by weight of the referenced layer,fails to dissolve in water at a temperature of 25° C. As used herein,the term “soluble” means that at least about 50% of the referencedlayer, more preferably at least about 75% of the referenced layer, bothby weight of the referenced layer, dissolves in water at a temperatureof 25° C.

[0051] The thickness of the inner layer may be important for ensuringthat the inner layer, and thus the inner core, remains intact until theform reaches the desired site of delivery, for example in the middle orlower intestinal tract. Wherein the inner layer is a continuous coatinghaving a coating weight of from about 3 mg/cm² to about 25 mg/vm², theinner coating weight may or may not be insoluble at a pH of about 3 orless. Preferably, however, wherein the inner layer has this coatingweight, the inner layer also exhibits an insolubility or solubility asdescribed herein above. Additionally or alternatively, it may bepreferable that the inner layer has a coating weight of from about 4mg/cm² to about 20 mg/cm².

[0052] Without intending to be limited by theory, it is preferred thatthe inner layer provides controlled release of the inner core, such thatrelease is accomplished at a location in the middle or lowergastrointestinal tract. The inner layer may prevent or minimize exposureof the susceptible inner core component to the buccal cavity, pharynx,esophagus, and stomach, and to the enzymes and other componentsassociated with these tissues.

[0053] The inner layer comprises one or more materials. Non-limitingexamples of preferred materials include zein, shellac, cellulosicpolymers and copolymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose methyl cellulose, ethylcellulose, cellulose acetate, cellulose acetate trimellitiate (CAT),hydroxypropylmethyl cellulose phthalate (HPMCP), cellulose acetatephthalate (CAP), hydroxypropylmethyl cellose succinate, andcarboxymethylcellulose sodium. Vinyl polymers and copolymers such aspolyvinyl acetate phthalate (PVAP), polyvinyl pyrollidone, polyvinylaceate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetatecopolymers.

[0054] Preferably, the inner layer comprises an anionic polymer. Themost preferred materials for use in the inner layer include copolymersof methacrylic acid, methacrylate, acrylic acid, or acrylate.Non-limiting examples of such copolymers include those marketed underthe term EUDRAGIT, commercially available from Rohm Pharma (Germany).These polymers and copolymers are particularly useful for targeteddelivery to the middle or lower gastrointestinal tract. For example,EUDRAGIT L 100-55, EUDRAGIT L 30 D-55 (soluble at pH of about 5.5 ormore), EUDRAGIT L 100 (soluble at pH of about 6 or more), and EUDRAGIT S100 (soluble at pH of about 7 or more), and like polymers. EUDRAGIT Scan be used on its own (i.e., free of other EUDRAGITS or other likematerials) for targeted delivery to the colon. Alternatively, EUDRAGITS, being poorly soluble in intestinal fluids below a pH of about 7, canbe used in combination with, for example, EUDRAGIT L-30D (soluble inintestinal fluids having a pH of about 5.5 or greater), in order toprovide a delayed relase composition which may deliver an inner corecomponent to various segments of the intestinal tract. For example,wherein more EUDRAGIT L-30D is used, delivery may commence in moreproximal segments of the small intestine, but wherein more EUDRAGIT S isused, delivery may commence in more distal segments of the smallintestine. In this example, it will be readily appreciated by thoseordinarily skilled in the art that both EUDRAGIT L-30D and EUDRAGIT Smay be replaced with other polymers or copolymers having similarsolubility profiles.

[0055] The inner layer is a preceding layer relative to the outer layer(i.e., the outer layer is a succeeding layer relative to the innerlayer). The inner layer may optionally be contiguous to the inner core,although one or more other layers may be preceding layers relative tothe inner layer. Preferably, the inner layer is contiguous to the(optional) capsule layer, wherein the capsule layer is also contiguousto the inner core (i.e., the inner layer is a succeeding layer relativeto the capsule layer).

[0056] The inner layer may optionally be contiguous to the outer layer,although one or more other layers may be succeeding layers relative tothe inner layer. Preferably, the inner layer is contiguous to the outerlayer.

[0057] Most preferably, the inner layer is contiguous to a capsule layer(and is a succeeding layer relative to the capsule layer) and is alsocontiguous to the outer layer (and is a preceding layer relative to theouter layer). In the most preferred embodiment herein, the compositioncomprises the inner core, a capsule layer, the inner layer, and theouter layer.

[0058] The Outer Layer

[0059] The outer layer is a continuous hydrophobic coating. As usedherein, the term “continuous” means that the layer is not disrupted by avoid at any point.

[0060] The outer layer therefore comprises one or more materials, suchthat the outer layer is hydrophobic.

[0061] In a preferred, but optional, embodiment of the presentinvention, the term hydrophobic, with reference to the outer layer,means that the outer layer exhibits a water vapor transmission rate(WVTR) of less than about 200 mg/m²/24 hours as measured using the ISOInternational Standard entitled “Sheet Materials—Determination of WaterVapour Transmission Rate—Gravimetric (Dish) Method” (Reference NumberISO 2528:1995(E)). In another embodiment, the term hydrophobic, withreference to the outer layer, means that the outer layer has a watervapor transmission rate (WVTR) of less than about 100 mg/m²/24 hoursusing this Standard.

[0062] Non-limiting examples of preferred materials that may be includedin the outer layer include fatty acids, fatty acid derivatives,polymers, and mixtures thereof. Most preferably, these materials arehydrophobic, such that the outer layer is made hydrophobic throughinclusion of this material. For example, the outer layer may comprise aslip aid (as described later herein).

[0063] Fatty acid derivatives can include fats (e.g., fatty acidglyceryl esters, e.g., hydrogenated vegetable oils) and waxes (e.g.,animal, fossil, vegetable, mineral, or synthetic waxes, such as camuba,beeswax, carob, candelilla, ozocerite, polyethylene waxes, paraffinwaxes, mixtures thereof, and the like). A wax is particularly preferred.Polymers can include polyvinylpyrrolidone, vinyl acetate, ethylcellulose, cellulose acetate phthalate (e.g., AQUATERIC), celluloseacetate trimelliate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,mixtures thereof, and the like. Most preferably, the outer layercomprises a material selected from the group consisting of fatty acids,fatty acid derivatives, and mixtures thereof.

[0064] In a optional embodiment herein the outer layer is a continuouscoating having a coating weight of from about 3 mg/cm² to about 25mg/cm², more preferably from about 4 mg/cm² to about 20 mg/cm².

[0065] The outer layer is joined to both the inner core and the innerlayer. The outer layer is a succeeding layer relative to the inner layer(i.e., the inner layer is a preceding layer relative to the outerlayer). The outer layer is not contiguous to the inner core. The outerlayer is contiguous to a preceding layer, wherein the preceding layer ispreferably the inner layer. Thus, one or more layers may optionallyintervene between the outer layer and inner layer. Also optionally, theouter layer may be a preceding layer relative to a layer that is evenfurther in proximity from the inner core. However, most preferably, theouter layer is the outermost layer relative to the inner core.

Optional Components of the Present Compositions

[0066] The compositions of the present invention may, independently,comprise additional optional components to enhance their performance.For example, one or more plasticizers, coloring agents, flavoringagents, sweeteners, anti-oxidants, buffering agents, slip aids, otherexcipients, and the like can be optionally included in the compositionsherein. Non-limiting examples of optional components are given below:

[0067] Plasticizers

[0068] Without intending to be limited by theory, plasticizers cause acomposition to become more easily deformed, less brittle, and/or lessprone to mechanical damage. Thus, one or more plasticizers mayoptionally be added to the present compositions, particularly a layer ofthe composition such that the layer is not susceptible to cracking(creation of voids) which can disrupt the continuous nature of thelayer.

[0069] Non-limiting examples of plasticizers include phthalates (e.g.,diethyl phthalate, dibutyl phthalate, dioctyl phthalate), citrates(e.g., triethyl citrate (e.g., CITROFLEX 2), acetyl triethyl citrate,tributyl citrate, and acetyl tributyl citrate), polyhydric alcohols,(e.g., sorbitol, glycerol), triacetin (glyceryl triacetate),polyethylene glycol (e.g., CARBOWAX 400), polysorbate 80, acetylatedmonoglycerides, glycerol, propylene glycol, fatty acid esters,surfactant polymers, camphor, silicone oil, castor oil, and mixturesthereof.

[0070] The amount of plasticizer used will vary, for example dependingon the plasticizer used and the desired character of the final layer(e.g., a soft gelatin layer or a hard gelatin layer). For example, in apreferred embodiment of the present compositions a layer comprising aplasticizer preferably comprises from about 1% to about 60%, morepreferably from about 5% to about 40% plasticizer, and most preferablyfrom about 10% to about 35% of the plasticizer, all by weight of thelayer comprising the plasticizer.

[0071] Coloring Agents

[0072] One or more pigments or other suitable coloring agents, such asdyes and lakes, may be incorporated into the compositions. U.S. FD&Cdyes (e.g., yellow #5, blue #2, red # 40) and/or U.S. FD&C lakes arepreferably used. Preferred lakes which may be used in the presentinvention include, for example, Lake red #40, yellow #6, blue #1, andthe like. Additionally, a mixture of U.S. FD&C dyes and/or U.S. FD&Clakes in combination with other conventional food and food colorants maybe used. As further examples, Riboflavin and β-carotene may also beused. Additionally, other natural coloring agents may be utilizedincluding, for example, fruit, vegetable, and/or plant extracts such asgrape, black currant, aronia, carrot, beetroot, red cabbage, andhibiscus.

[0073] The coloring agents used herein may be independently utilized inthe inner core, the inner layer, the outer layer, and/or any otherlayers or components of the present compositions (e.g., the capsulelayer, if present). For example, one or more coloring agents may be usedin the layer that is least proximal to the inner core in order to imparta desired appearance to the finished composition.

[0074] The amount of coloring agent used will vary, depending on theagents used and the character or intensity desired in the finishedcomposition. One of ordinary skill in the art will readily make suchdetermination.

[0075] Flavoring Agents

[0076] One or more flavoring agents may be incorporated in thecompositions of the present invention in order to enhance theirpalatability, particularly as a component of the layer that is leastproximal to the inner core. Any natural or synthetic flavor agent can beused in the present invention. As used herein, such flavors may besynthetic or natural flavors.

[0077] For example, one or more botanical and/or fruit flavors may beutilized herein. Particularly preferred fruit flavors are exotic andlactonic flavors such as, for example, passion fruit flavors, mangoflavors, pineapple flavors, cupuacu flavors, guava flavors, cocoaflavors, papaya flavors, peach flavors, and apricot flavors. Besidesthese flavors, a variety of other fruit flavors can be utilized such as,for example, apple flavors, citrus flavors, grape flavors, raspberryflavors, cranberry flavors, cherry flavors, grapefruit flavors, and thelike. These fruit flavors can be derived from natural sources such asfruit juices and flavor oils, or may alternatively be syntheticallyprepared.

[0078] The flavoring agents used herein may be independently utilized inthe inner core, the inner layer, the outer layer, and/or any otherlayers or components of the present compositions (e.g., the capsulelayer, if present). For example, one or more flavoring agents may beused in the layer that is least proximal to the inner core in order toimpart a desired flavor to the finished composition.

[0079] The amount of flavoring agent used will vary, depending on theagents used and the character or intensity desired in the finishedcomposition. One of ordinary skill in the art will readily make suchdetermination.

[0080] Sweeteners

[0081] One or more sweeteners, including for example carbohydratesweeteners and natural and/or artificial no/low calorie sweeteners mayoptionally be used herein. For example, the compositions of the presentinvention can be sweetened with any of the carbohydrate sweeteners,preferably monosaccharides and/or disaccharides. Preferred sugarsweeteners for use in the compositions of the present invention aresucrose, fructose, glucose, maltose, and mixtures thereof.

[0082] One or more high intensity sweeteners may be utilized,particularly as a component of the layer that is least proximal to theinner core. For example, one or more of the following sweeteners may beutilized: saccharin, cyclamates, L-aspartyl-L-phenylalanine lower alkylester sweeteners (e.g., aspartame); L-aspartyl-D-alanine amidesdisclosed in U.S. Pat. No. 4,411,925; L-aspartyl-D-serine amidesdisclosed in U.S. Pat. No. 4,399,163;L-aspartyl-L-1-hydroxymethylalkaneamide sweeteners disclosed in U.S.Pat. No. 4,338,346; L-aspartyl-1-hydroxyethyalkaneamide sweetenersdisclosed in U.S. Pat. No. 4,423,029; L-aspartyl-D-phenylglycine esterand amide sweeteners disclosed in European Patent Application 168,112,published Jan. 15, 1986;N-[N-3,3-dimethylbutyl)-L-alpha-aspartyl]-L-phenylalanine 1-methyl estersweeteners disclosed in WO 99/30576; thaumatin; dihydrochalcones;cyclamates; steviosides; glycyrrhizins, synthetic alkoxy aromatics;sucralose; suosan; miraculin; monellin; sorbitol, xylitol; talin;cyclohexylsulfamates; substituted imidazolines; synthetic sulfamic acidssuch as acesulfame, acesulfame K and n-substituted sulfamic acids;oximes such as perilartine; peptides such as aspartyl malonates andsuccanilic acids; dipeptides; amino acid based sweeteners such asgem-diaminoalkanes, meta-aminobenzoic acid, L-aminodicarboxylic acidalkanes, and amides of certain alpha-aminodicarboxylic acids andgem-diamines; and 3-hydroxy-4-alkyloxyphenyl aliphatic carboxylates orheterocyclic aromatic carboxylates; erythritol; and mixtures thereof.Aspartame is particularly preferred.

[0083] The sweeteners used herein may be independently utilized in theinner core, the inner layer, the outer layer, and/or any other layers orcomponents of the present compositions (e.g., the capsule layer, ifpresent). For example, one or more sweeteners may be used in the layerthat is least proximal to the inner core in order to impart a desiredsweet character to the finished composition. As a further example, asweetener may be independently utilized as a component of the innercore, for example, as an excipient.

[0084] The amount of sweetener used will vary, depending on the agentsused and the character or intensity desired in the finished composition.One of ordinary skill in the art will readily make such determination.

[0085] Anti-Oxidants

[0086] One or more anti-oxidants may be utilized in the compositions ofthe present invention. Naturally occurring as well as syntheticanti-oxidants may be used. Non-limiting examples of naturalanti-oxidants include tocopherols (e.g., vitamin E), ascorbic acid(e.g., vitamin C), vitamin A (e.g., beta-carotene), grape seed extract,selenium, and coenzyme Q10. Non-limiting examples of syntheticanti-oxidants include butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), and propyl gallate. Most preferably, theanti-oxidant is mixed with a component of the inner core.

[0087] Buffering Agents

[0088] One or more buffering agents may be utilized in the compositionsof the present invention in order to, for example, maintain a constantpH within an environment. For example, acetate buffers, citrate buffers,and phosphate buffers may be used. Non-limiting examples include aceticacid, sodium acetate, citric acid, sodium citrate, monobasic sodiumphosphate, dibasic sodium phosphate, and sodium chloride. Mostpreferably, the buffering agent is mixed with a component of the innercore.

[0089] Slip Aids

[0090] One or more slip aids may optionally be included in the presentcompositions to improve surface friction, water resistance, abrasionresistance, and/or other mechanical properties of the composition. Forexample, a slip aid may be included in the layer that is least proximalto the inner core, such that a mammal can more easily swallow thecomposition when orally administered.

[0091] Non-limiting examples of slip aids that may be used include waxadditives including, for example, animal, fossil, vegetable, mineral, orsynthetic waxes. Preferred wax additives include carnuba, beeswax,carob, candelilla, ozocerite, polyethylene waxes, paraffin waxes,polypropylene waxes, and the like. Other non-limiting examples includesurfactants, glycerin, oils, and polyethylene glycols.

[0092] The slip aids used herein may be independently utilized in theinner core, the inner layer, the outer layer, and/or any other layers orcomponents of the present compositions (e.g., the capsule layer, ifpresent). For example, one or more slip aids is preferably used in thelayer that is least proximal to the inner core. As has been mentioned,the outer layer is preferably this least proximal layer, and a slip aidis often the component utilized therein in order to enhance ease ofadministration as well as impart the desired hydrophobicity.

[0093] The amount of slip aid used will vary, depending on the aid usedand the specific purpose of the aid. One of ordinary skill in the artwill readily make such determination.

[0094] Printed Material

[0095] The compositions herein may optionally comprise printed material.For example, the composition may comprise text, words, pictures,symbols, and/or other visible images that may or may not convey usefulinformation to the manufacturer and/or consumer. To illustrate, acapsule may indicate dosage level of a biologically active component, ormay indicate a trademark or other like descriptor. Typically, if used,such printed material is printed on the surface of the layer that isleast proximate relative to the inner core. Material will be printed onthe surface of a composition herein via a variety of well-known methods,for example, passing a capsule over an embossed roller which transfersthe material to the capsule.

Methods of Using the Present Compositions

[0096] Methods of using the present compositions comprise orallyadministering (i.e., through ingestion) a composition of the presentinvention to a mammal, preferably a human, to provide various healthbenefits. The specific health benefit provided will typically bedependent upon the character of the inner core, as well as that of theinner layer. Frequency of administration is not limited and may bedependent upon the specific character of the composition and the desiredhealth benefits. For example, where the inner core comprises bacteria,certain health benefits may result and be preferred, for example,treatment of inflammation, undesirable gastrointestinal activity,inflammatory bowel disease, irritable bowel syndrome, Crohn's disease,ulcerative colitis, post-infection colitis, and pouchitis. See e.g., WO00/42168 and WO 00/41707.

[0097] As used herein, the term “orally administering” with respect tothe mammal (preferably, human) means that the mammal ingests or isdirected to ingest one or more compositions of the present invention.Wherein the mammal is directed to ingest one or more of thecompositions, such direction may be that which instructs and/or informsthe user that use of the composition may and/or will provide one or moregeneral health benefits. For example, such direction may be oraldirection (e.g., through oral instruction from, for example, aphysician, health professional, sales professional or organization,and/or radio or television media (i.e., advertisement) or writtendirection (e.g., through written direction from, for example, aphysician or other health professional (e.g., scripts), salesprofessional or organization (e.g., through, for example, marketingbrochures, pamphlets, or other instructive paraphernalia), written media(e.g., internet, electronic mail, or other computer-related media),and/or packaging associated with the composition (e.g., a label presenton a package containing the composition). As used herein, “written”means through text, words, pictures, symbols, and/or other visibleimages.

Method of Making the Present Compositions

[0098] The present compositions may be made in accordance with methodswhich will be well understood in the art, given the guidance of thisdisclosure. Detailed information relating to materials, equipment, andprocesses for preparing coated dosage forms may be found inPharmaceutical Dosage Forms: Tablets, Eds. Lieberman et al., (New York,Marcel Dekker, Inc., 1989) and Ansel et al., Pharmaceutical Dosage Formsand Drug Delivery Systems, 6^(th) Ed., Media, PA, Williams & Wilkins,1995). For example, preparation of the various layers and coating ofcapsules is well documented, and may often be categorized as follows:

[0099] (a) air suspension coating (e.g., utilizing fluid bed drying);

[0100] (b) pan coating (e.g., utilizing a rotating drum); and

[0101] (c) dip coating (e.g., dipping a capsule into a solution or meltof a material).

[0102] The layers described herein may be applied as a solution, whereina solvent is allowed to volatize, thereby leaving behind a dry coat, orby utilizing a melt wherein the layer is applied warm and allowed tocool.

[0103] However, with respect to preparation of the multiple-layeredcompositions of the present invention, certain considerations should beattended with care. For example, wherein the outer layer is contiguousto the inner layer, the outer layer should be applied withoutsubstantial compromise to, or disturbance of, the established innerlayer. To illustrate, wherein the inner layer could be solubilized bythe solvent used to apply the outer layer, then the outer layer shouldbe applied such that most of this solvent is removed prior to thesolution coming into contact with the inner layer. This may be achievedby spraying the outer layer onto the continuous inner layer (whichsurrounds the inner core and, optionally, the capsule layer). Thesolvent will substantially evaporate during such spraying. Alternativelyor additionally, for example, one may ensure that the inner layer is notmechanically damaged during application of the outer layer. Such damagemay occur during air suspension or pan coating, wherein the individualdose forms are tumbled together and/or may contact the walls of thecoating device. In these situations, it may be advantageous to includeone or more plasticizers as part of the inner layer, to reducebrittleness and enable the layer to become more mechanically robust.

[0104] Alternatively or additionally, one may ensure that the inner corewill not melt and fluidize at temperatures utilized to apply the variouslayers of the present compositions. If such melting is a possibility,the coating process(es) should be performed quickly to minimizefluidization of the inner core.

EXAMPLES

[0105] The following are non-limiting examples of the presentcompositions, which are prepared utilizing conventional methods. Thefollowing examples are provided to illustrate the invention and are notintended to limit the scope thereof in any manner.

Example 1

[0106] A composition in accordance with the present invention isprepared as follows. Five (5) kilograms of hard, banded, two-piecehydroxypropylmethylcellulose (HPMC) capsules (size 3), each containingan inner core comprising about 180 milligrams of freeze-dried probioticformulation (comprising about 10¹⁰ cfu of Bifidobacterium infantis) areobtained. The capsules are tumbled in a pan having an inner diameter ofabout 25 inches. While maintaining the capsule bed temperature atapproximately 25° C., a first coating formulation is sprayed onto thecapsules with an in-process evaporation rate of at least about 2.5grams/minute/kilogram of the capsules, which spraying forms the innerlayer. The coating formulation is maintained at a temperature of about40° C. and comprises EUDRAGIT L30D55 (about 70%, by weight of the firstcoating formulation), triethyl citrate (about 5%, by weight of the firstcoating formulation), TWEEN 80 (about 30% aqueous solution, by weight)(about 1%, by weight of the first coating formulation), and about 24%water. Upon achieving a coating weight of about 8 mg/cm², the capsulescoated with the inner layer are subjected to a final drying at about 40°C. for about 5 minutes.

[0107] The outer layer is then applied as follows. The coated capsulesare tumbled at a temperature of from about 35° C. to about 40° C. in aseparate pan having an internal diameter of about 25 inches. Finelypowdered carnuba wax (having a particle size of from about 100 micronsto about 150 microns) is slowly added to the tumbling capsules until acoating weight of about 10 mg/cm² is achieved. The composition of thisexample therefore comprises the inner core, a capsule layer, the innerlayer, and the outer layer.

Examples 2-5

[0108] A visually appealing capsule is prepared in accordance withExample 1, except that the coating formulation used to prepare the innerlayer is modified as follows (with all levels expressed in weightpercentage, by weight of the coating formulation): Example 2 Example 3Example 4 Example 5 EUDRAGIT L30D55 EUDRAGIT S100 EUDRAGIT L100Hydroxypropylmethyl (about 50%) (about 20%) (about 65%) CellulosePhthalate (about 50%) Polyethylene Glycol Polyethylene Glycol TriethylCitrate (about Glycerol (about 5%) (about 5%) (about 7.5%) 5%) TitaniumDioxide (about Titanium Dioxide (about Titanium Dioxide (about TitaniumDioxide (about 1%) 0.5%) 0.25%) 0.25%) Water (about 44%) FD&C Red #40(about FD&C Lake Blue #1 beta-Carotene (about 0.5%) (about 0.25%) 3%)Acetone (about 71.5%) Talc (about 2.5%) Potassium Sorbate (about 0.1%)Water (about 27%) Sodium Lauryl Sulfate (about 1.5%) Water (about40.15%)

[0109] The resulting inner layers result in compositions that enhanceconsumer or patient acceptability and increased dosing compliance, dueto the visually appealing coatings.

Examples 6-9

[0110] Organoleptically appealing capsules are prepared in accordancewith Examples 1, 2, 3, 4 or 5, except that the coating formulation usedto prepare the outer layer is modified as follows (with all levelsexpressed in weight percentage, by weight of the coating formulationused to prepare the outer layer): Example 6 Example 7 Example 8 Example9 Carnuba Wax (about Paraffin Wax (about Carnuba Wax (about Carnuba Wax(about 95%) 92%) 88%) 90%) ASPARTAME (about Cyclamate (about 1%)Ozocerite (about 1%) Sucralose (about 1%) 0.5%) Orange Flavor, Coolant(about 1%) Acesulfame K (about Talc (about 6%) powdered (about 4.5%) 2%)Peppermint Flavor, Cocoa Flavor (about Peppermint Flavor, spray dried(about 6%) 9%) spray dried (about 3%)

[0111] The resulting outer layers result in compositions that enhanceconsumer or patient acceptability and increased dosing compliance, dueto the organoleptically appealing coatings.

Example 10

[0112] In a modification of the process set forth in Example 1, theouter layer is applied to the capsule using a dip coating process. Thecapsule comprising the inner core, capsule layer, and inner layer issubmerged into melted wax. Once removed, the wax is allowed to solidify.This process is repeated until a continuous coating is produced.

Example 11

[0113] In a specific example of the dip coating process used inaccordance with Example 10, the inner core comprises acetylsalicylicacid, and is encapsulated by the HPMC capsule layer. The inner layer isprepared, surrounding the capsule layer, and is allowed to dry. Thiscapsule is then dip coated in beeswax at a temperature of about 90° C.,then allowed to cool.

What is claimed is:
 1. A composition comprising: (a) an inner corecomprising one or more components; (b) an inner layer which is joined tothe inner core, wherein the inner layer is selected from the groupconsisting of continuous coatings which are insoluble at a pH of about 3or less, continuous coatings having a coating weight of from about 3mg/cm² to about 25 mg/cm², and combinations thereof; and (c) an outerlayer which is joined to the inner core, wherein the outer layer is acontinuous hydrophobic coating; wherein the inner layer is a precedinglayer relative to the outer layer.
 2. The composition according to claim1 wherein the inner layer is a continuous coating soluble at a pH ofabout 5 or more.
 3. The composition according to claim 2 wherein theouter layer exhibits a water vapor transmission rate of less than about200 mg/m²/24 hours and comprises a material selected from the groupconsisting of fatty acids, fatty acid derivatives, polymers, andmixtures thereof.
 4. The composition according to claim 3 wherein theinner layer is soluble at a pH of about 5.5 or more.
 5. The compositionaccording to claim 4 further comprising a capsule layer, wherein theinner layer is contiguous to the capsule layer and the capsule layer iscontiguous to the inner core.
 6. The composition according to claim 5wherein the inner layer comprises an anionic polymer.
 7. The compositionaccording to claim 6 wherein the anionic polymer is a copolymer ofmethacrylic acid, methacrylate, acrylic acid, or acrylate.
 8. Thecomposition according to claim 7 wherein the outer layer comprises amaterial selected from the group consisting of fatty acids, fatty acidderivatives, and mixtures thereof.
 9. The composition according to claim8 wherein at least one of the inner layer and outer layer comprises aplasticizer.
 10. The composition according to claim 8 wherein at leastone of the inner layer and outer layer has a coating weight of fromabout 4 mg/cm² to about 20 mg/cm².
 11. The composition according toclaim 8 wherein the outer layer comprises a component selected from thegroup consisting of coloring agents, flavoring agents, sweeteners,anti-oxidants, buffering agents, surfactants, talc, and mixturesthereof.
 12. The composition according to claim 1 wherein the inner corecomprises bacteria.
 13. The composition according to claim 12 whereinthe inner layer is soluble at a pH of about 5 or more.
 14. Thecomposition according to claim 13 wherein the outer layer exhibits awater vapor transmission rate of less than about 200 mg/m²/24 hours andcomprises a material selected from the group consisting of fatty acids,fatty acid derivatives, polymers, and mixtures thereof.
 15. Thecomposition according to claim 14 wherein the inner layer is soluble ata pH of about 5.5 or more.
 16. The composition according to claim 15further comprising a capsule layer, wherein the inner layer iscontiguous to the capsule layer and the capsule layer is contiguous tothe inner core.
 17. The composition according to claim 16 wherein theinner layer comprises an anionic polymer.
 18. The composition accordingto claim 17 wherein the anionic polymer is a copolymer of methacrylicacid, methacrylate, acrylic acid, or acrylate
 19. The compositionaccording to claim 18 wherein the outer layer comprises a materialselected from the group consisting of fatty acids, fatty acidderivatives, and mixtures thereof.
 20. The composition according toclaim 19 wherein the outer layer comprises a material selected from thegroup consisting of fatty acids, fatty acid derivatives, and mixturesthereof.
 21. The composition according to claim 20 wherein at least oneof the inner layer and outer layer comprises a plasticizer.
 22. Thecomposition according to claim 21 wherein at least one of the innerlayer and outer layer has a coating weight of from about 4 mg/cm² toabout 20 mg/cm².
 23. The composition according to claim 21 wherein theouter layer comprises a component selected from the group consisting ofcoloring agents, flavoring agents, sweeteners, anti-oxidants, bufferingagents, surfactants, talc, and mixtures thereof.
 24. The compositionaccording to claim 1 wherein the inner core comprises bacteria, whereinat least a plurality of the bacteria is selected from the groupconsisting of lactobacillus, bifidobacteria, and mixtures thereof. 25.The composition according to claim 24 wherein the inner layer is solubleat a pH of about 5 or more.
 26. The composition according to claim 25wherein the outer layer exhibits a water vapor transmission rate of lessthan about 200 mg/m²/24 hours comprises a material selected from thegroup consisting of fatty acids, fatty acid derivatives, polymers, andmixtures thereof.
 27. The composition according to claim 26 wherein theinner layer is soluble at a pH of about 5.5 or more.
 28. The compositionaccording to claim 27 further comprising a capsule layer, wherein theinner layer is contiguous to the capsule layer and the capsule layer iscontiguous to the inner core.
 29. The composition according to claim 28wherein the inner layer comprises an anionic polymer.
 30. Thecomposition according to claim 29 wherein the anionic polymer is acopolymer of methacrylic acid, methacrylate, acrylic acid, or acrylate31. The composition according to claim 30 wherein the outer layercomprises a material selected from the group consisting of fatty acids,fatty acid derivatives, and mixtures thereof.
 32. The compositionaccording to claim 31 wherein the outer layer comprises a materialselected from the group consisting of fatty acids, fatty acidderivatives, and mixtures thereof.
 33. The composition according toclaim 32 wherein at least one of the inner layer and outer layercomprises a plasticizer.
 34. The composition according to claim 32wherein at least one of the inner layer and outer layer has a coatingweight of from about 4 mg/cm² to about 20 mg/cm².
 35. The compositionaccording to claim 32 wherein the outer layer comprises a componentselected from the group consisting of coloring agents, flavoring agents,sweeteners, anti-oxidants, buffering agents, surfactants, talc, andmixtures thereof.